IL-6–mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation
Ping Zhang, … , Geoffrey R. Hill, Siok-Keen Tey
Ping Zhang, … , Geoffrey R. Hill, Siok-Keen Tey
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e174184. https://doi.org/10.1172/JCI174184.
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Research Article

IL-6–mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation

Abstract

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell–specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ–dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.

Authors

Ping Zhang, Peter Fleming, Christopher E. Andoniou, Olivia G. Waltner, Shruti S. Bhise, Jose Paulo Martins, Benjamin A. McEnroe, Valentina Voigt, Sheridan Daly, Rachel D. Kuns, Adaeze P. Ekwe, Andrea S. Henden, Alda Saldan, Stuart Olver, Antiopi Varelias, Corey Smith, Christine R. Schmidt, Kathleen S. Ensbey, Samuel R.W. Legg, Tomoko Sekiguchi, Simone A. Minnie, Mark Gradwell, Irma Wagenaar, Andrew D. Clouston, Motoko Koyama, Scott N. Furlan, Glen A. Kennedy, E Sally Ward, Mariapia A. Degli-Esposti, Geoffrey R. Hill, Siok-Keen Tey

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Figure 3

IL-6 signaling promotes the loss of recipient IgG.

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IL-6 signaling promotes the loss of recipient IgG. (A–D) Latently infect...
(A–D) Latently infected B6D2F1 recipient mice were transplanted with BM (5 × 106) and T cells (2 × 106) from uninfected B6.Cd4Cre+ Il6rfl/fl (Cre+) mice or littermate controls (Cre–) and analyzed 4–5 weeks after BMT (n = 14 per group from 3 experiments). (A) MCMV-specific IgG titers. (B) Correlation between MCMV-specific IgG titers and viral load in plasma and liver. (C and D) Titers of MCMV-specific IgG1 and IgG3 (C) and IgG2 allotypes (D). Dashed lines indicate limit of detection. (E) Experimental schema for the quantification of IgG clearance by flow cytometry and (F) representative standard curve. (G) Noninfected B6D2F1 mice were transplanted with Cd4Cre+ Il6rfl/fl BM (5 × 106) plus T cells (2 × 106) (Cre+, n = 10, orange) or with Cd4Cre– Il6rfl/fl (Cre–) BM plus T cells from littermate control mice, the latter with or without CSA to limit GVHD (Cre–, n = 12, blue; or Cre– plus CSA, n = 8, green). Mice transplanted with TCD Cd4Cre– Il6rfl/fl BM alone (TCD, n = 5, black) and nontransplanted mice (non-BMT, n = 6, red) were used as controls. The half-life (from days 7–21) of administered IgG2b was calculated for each individual mouse and compared between the indicated groups. Conc., concentration. Data were combined from 2 experiments. Data re presented as the median ± IQR and were analyzed with the Mann-Whitney U test (*P < 0.05 and **P < 0.01).